First-Line Bevacizumab Does Not Improve Survival in Glioblastoma

Mark R. Gilbert, MD

A phase III study has found that adding bevacizumab to a standard treatment regimen for glioblastoma consisting of chemoradiation with temozolomide in newly diagnosed patients does not improve overall survival (OS) and did not significantly improve progression-free survival (PFS), suggesting that while there may be a modest benefit, the drug may be best suited for patients with recurrent disease, a setting for which the drug is already approved.

The results of the phase III RTOG 0825 study were presented at the 49th Annual American Society of Clinical Oncology (ASCO) Meeting, held from May 31-June 4, 2013, in Chicago, Illinois.

Bevacizumab is monoclonal antibody that halts angiogenesis, or the formation of blood vessels, by blocking vascular endothelial growth factor-A (VEGF-A), which is produced by glioblastoma to stimulate blood vessel growth.

“Since angiogenesis is such a prominent feature of glioblastoma, it seems a very logical target,” said Mark R. Gilbert, MD, a professor of neuro-oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas, and lead author of the study.

The drug received approval from the FDA to treat recurrent glioblastoma based on positive data obtained from a number of phase II clinical trials. Occasionally, bevacizumab is prescribed as a first-line treatment for patients with glioblastoma, the most common malignant primary brain tumor. This trial was designed to determine whether the drug was effective if given in an earlier setting.

In this trial, 637 patients with newly diagnosed glioblastoma were randomized to receive eitherstandard chemoradiation therapy with a placebo or standard chemoradiation therapy plus bevacizumab in a dose of 10mg/kg intravenously every two weeks. The trial was designed to allow for patients to cross over to the placebo group or continue with bevacizumab if their disease progressed, which Gilbert explained was done because bevacizumab is currently offered in recurrent disease.¹

Median OS and PFS were co-primary endpoints. Gilbert explained that since a P value of .05 signifies statistical significance, the investigators in this study split the value among the two co-primary endpoints, so a P value of .046 was required for statistical significance for median OS and a value of .004 was required for significance in PFS.

The difference in median OS was not statistically significant between the two study arms. The median OS in the bevacizumab arm was 15.7 months compared with 16.1 months in the placebo arm (P = .21). The median PFS was 10.7 months in the bevacizumab arm and 7.3 months in the placebo arm (P = .007), but the difference in PFS did not reach the preset level of significance assigned to this study.

Dr. Gilbert Describes Ongoing RTOG 0825 Trial Analyses

The researchers performed a subgroup analysis based on MGMT methylation status and a nine-gene expression signature, but they were unable to determine whether there was a selective benefit. Additionally, Gilbert said the study found that patients on the bevacizumab arm had a significant worsening of quality of life over time compared with patients in the placebo arm.

“We feel that bevacizumab remains an important therapy for patients with glioblastoma, but the results of this study do not support its upfront use,” Gilbert said.

The RTOG 0825 study is one of two similar phase III trials designed to evaluate the efficacy of bevacizumab in patients with glioblastoma, and it is also the second to show only a modest improvement in PFS. The results of the other trial, the phase III AVAglio study, were first presented at the 17th Annual Scientific Meeting & Education Day of the Society for Neuro-Oncology, held in November 2012 in Washington, DC. In that study, the median PFS was 10.6 months compared with 6.2 months in the group that received only radiotherapy and temozolomide (HR = 0.64; 95% CI, 0.55—0.74; P < .0001).²

An analysis of health-related quality of life in the AVAglio study presented at the 2013 ASCO meeting,found that patients who received bevacizumab had delayed time to definitive deterioration compared with patients in the placebo arm (P < .0001). Karnofsky performance status was stable or improved during the period of PFS in both arms of the study.³ Physical functioning, social functioning, motor dysfunction, and communication deficit were all improved in patients who received the combination.

Gilbert explained that the methods used to analyze quality of life in the AVAglio study were different than those used in the RTOG 0825 study, which could account for why an improvement in quality of life was observed in one study and not the other.

References

1. Gilbert MR, Dignam J, Won M, et al. RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). J Clin Oncol. 2013;31(suppl; abstr 1).
2. Chinot O, Wick W, Mason W, et al. Phase III trial of bevacizumab added to standard radiotherapy and temozolomide for newly-diagnosed glioblastoma: mature progression-free survival and preliminary overall survival results in AVAglio. Neuro Oncol. 2012; 14:vi101-vi105. Abstract OT-3.
3. Henriksson R, Bottomley A, Mason W, et al. Progression-free survival (PFS) and health-related quality of life (HRQoL) in AVAglio, a phase III study of bevacizumab (Bv0, temozolomide (T), and radiotherapy (RT) in newly diagnosed glioblastoma (GBM). J Clin Oncol. 2013;31(suppl; abstr 2005).

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